The monocyte/macrophage (M/M) system represents an important target of HIV infection. A number of cytokines have been shown to influence HIV infection. We have demonstrated that CD8+ T-cell derived soluble factor(s), other than beta chemokines RANTES, MIP-1alpha and MIP-1beta (which were recently shown to suppress HIV infection in T cells), are capable of suppressing HIV replication in the M/M system. The anti-HIV activity of the supernatants from CD8+ T-cell cultures is likely to be mediated by unknown or uncharacterized cytokines(s) because neutralization of interleukin (IL)-10, IL-13, interferon (IFN)-alpha, and IFN-gamma (which are known to inhibit HIV replication in macrophages) did not abolish this activity. Identification of the anti-HIV factor(s) will likely contribute to a better understanding of HIV pathogenesis as well as have implications for the development of new therapeutic strategies. Another important aspect of HIV infection of the M/M system is the differential susceptibility of the cells belonging to the M/M system to HIV infection, depending on virus strains, cellular differential status, or cellular localization in vivo. First, certain types of HIV strains replicate well in macrophages (M-tropic), while others replicate only in CD4+ T cells (T-tropic). Second, promonocytes and monocytes are much less susceptible to HIV infection than mature macrophages. Finally, macrophages in certain tissues such as brain, skin, and the gastrointestinal tract harbor HIV more frequently than those in other tissues such as liver. Not only are cells of the M/M system differentially susceptible to HIV infection, they respond differently to RANTES, MIP-1alpha and MIP-1beta. In this regard, these chemokines can suppress HIV in freshly isolated monocytes but not in mature macrophages. In order to address these issues, we have established an in vitro experimental system using promonocytic U937 cell clones.